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RNA splicing and editing modulation of 5-HT2C receptor function: relevance to anxiety and aggression in VGV mice

Molecular Psychiatry volume 18, pages 656–665 (2013)Cite this article

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Abstract

Changes in serotonin2C receptor (5-HTR2c) editing, splicing and density were found in conditions such as depression and suicide, but mechanisms explaining the changes in 5-HTR2c function are unknown. Thus, mice expressing only the fully edited VGV isoform of 5-HTR2c, in which clinically relevant behavioral changes are associated with alterations in splicing and receptor density, were studied. VGV mice displayed enhanced anxiety-like behavior in response to a preferential 5-HTR2c agonist in the social interaction test. Nearly half of interactions between pairs of VGV congeners consisted of fighting behaviors, whereas no fighting occurred in wild-type (WT) mice. VGV mice also exhibited a striking increase in freezing behaviors in reaction to an innately aversive ultrasonic stimulus. This behavioral phenotype occurred in conjunction with decreased brain 5-HT turnover during stress. These functional data were put in relation with the 5-HTR2c mRNA splicing process generating a truncated protein (5-HTR2c-Tr) in addition to the full-length receptor (5-HTR2c-Fl). 5-HTR2c-Tr mRNA was less abundant in many brain regions of VGV mice, which concomitantly had more 5-HTR2c than WT mice. Fluorescence resonance energy transfer and bioluminescence resonance energy transfer studies in transfected living HEK293T cells showed that 5-HTR2c-Tr interacts with 5-HTR2c-Fl. The 5-HTR2c-Tr was localized in the endoplasmic reticulum where it retained 5-HTR2c-Fl, preventing the latter to reach the plasma membrane. Consequently, 5-HTR2c-Tr decreased 3H-mesulergine binding to 5-HTR2c-Fl at the plasma membrane in a concentration-dependent manner and more strongly with edited 5-HTR2c-Fl. These results suggest that 5-HTR2c pre-mRNA editing and splicing are entwined processes determining increased 5-HTR2c levels in pathological conditions through a deficit in 5-HTR2c-Tr.

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Acknowledgements

We thank Dr K Nishikura and The Wistar Institute (PA) for providing the VGV mice. This research was supported by INSERM, Université Pierre et Marie Curie, European Community DevAnx (Health: F2-2007-201714) Program and ANR contract «Sercedit» (ANR-06-Neuro-045-01). CBP Martin was recipient of a fellowship from the French Ministère de la Recherche.

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  1. C B P Martin and F Ramond: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM U894, Centre de Psychiatrie et de Neuroscience, UPMC, Fac. Med. Pierre and Marie Curie, Site Pitié-Salpêtrière, Paris, France

    C B P Martin, C Chevarin, L Lanfumey, M Hamon & R Mongeau

  2. Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, Université Claude Bernard Lyon 1, Lyon, France

    F Ramond, A-S Berthiau, S Caussanel & J J Madjar

  3. New York State Department of Health, Wadsworth Center, Albany, NY, USA

    D T Farrington

  4. Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    A S Aguiar Jr

  5. Department of Psychiatry, Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY, USA

    K Herrick-Davis

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Martin, C., Ramond, F., Farrington, D. et al. RNA splicing and editing modulation of 5-HT2C receptor function: relevance to anxiety and aggression in VGV mice. Mol Psychiatry 18, 656–665 (2013). https://doi.org/10.1038/mp.2012.171

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